EA032301B1 - Изоиндолиновые или изохинолиновые соединения, способ их получения и содержащие их фармацевтические композиции - Google Patents

Info

Publication number

EA032301B1

EA032301B1 EA201600122A EA201600122A EA032301B1 EA 032301 B1 EA032301 B1 EA 032301B1 EA 201600122 A EA201600122 A EA 201600122A EA 201600122 A EA201600122 A EA 201600122A EA 032301 B1 EA032301 B1 EA 032301B1

Authority

EA

Eurasian Patent Office

Prior art keywords

methyl

tetrahydroisoquinoline

carbonyl

hydroxyphenyl

group

Prior art date

2013-07-23

Links

• Espacenet
• Global Dossier
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• 238000000034 method Methods 0.000 title claims description 543
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
• 238000002360 preparation method Methods 0.000 title description 3
• GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 title description 2
• 230000008569 process Effects 0.000 title description 2
• 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 100
• 239000003814 drug Substances 0.000 claims abstract description 6
• -1 1,3-thiazolyl group Chemical group 0.000 claims description 351
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 294
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 190
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 188
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 174
• 239000000203 mixture Substances 0.000 claims description 165
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 93
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 46
• 125000003118 aryl group Chemical group 0.000 claims description 42
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
• 150000007942 carboxylates Chemical class 0.000 claims description 30
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
• 229910052757 nitrogen Inorganic materials 0.000 claims description 23
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 16
• 239000002253 acid Substances 0.000 claims description 15
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 14
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
• 150000003839 salts Chemical class 0.000 claims description 14
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 13
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
• 206010028980 Neoplasm Diseases 0.000 claims description 12
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 12
• 201000011510 cancer Diseases 0.000 claims description 11
• 125000001072 heteroaryl group Chemical group 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 10
• 102000004169 proteins and genes Human genes 0.000 claims description 10
• 108090000623 proteins and genes Proteins 0.000 claims description 10
• 239000000460 chlorine Substances 0.000 claims description 9
• 125000002619 bicyclic group Chemical group 0.000 claims description 8
• 125000004432 carbon atom Chemical group C* 0.000 claims description 8
• MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 7
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
• 125000000217 alkyl group Chemical group 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 125000002950 monocyclic group Chemical group 0.000 claims description 6
• 125000001424 substituent group Chemical group 0.000 claims description 6
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
• 206010041067 Small cell lung cancer Diseases 0.000 claims description 5
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 5
• 208000000587 small cell lung carcinoma Diseases 0.000 claims description 5
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
• 208000023275 Autoimmune disease Diseases 0.000 claims description 4
• 208000026310 Breast neoplasm Diseases 0.000 claims description 4
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 4
• 206010033128 Ovarian cancer Diseases 0.000 claims description 4
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
• 206010060862 Prostate cancer Diseases 0.000 claims description 4
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
• 125000002837 carbocyclic group Chemical group 0.000 claims description 4
• 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
• 201000010099 disease Diseases 0.000 claims description 4
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
• 229910052736 halogen Inorganic materials 0.000 claims description 4
• 150000002367 halogens Chemical class 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
• 230000003211 malignant effect Effects 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 201000000050 myeloid neoplasm Diseases 0.000 claims description 4
• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
• 125000004043 oxo group Chemical group O=* 0.000 claims description 4
• 229910052717 sulfur Inorganic materials 0.000 claims description 4
• 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 4
• GNFLFHZJXXFDRA-UHFFFAOYSA-N 1,2-dimethylpyrrole Chemical compound CC1=CC=CN1C GNFLFHZJXXFDRA-UHFFFAOYSA-N 0.000 claims description 3
• DRXOPQFEWDRGKT-UHFFFAOYSA-N 1,5-dimethylpyrrole-2-carbonitrile Chemical compound CC1=CC=C(C#N)N1C DRXOPQFEWDRGKT-UHFFFAOYSA-N 0.000 claims description 3
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 3
• NPDACUSDTOMAMK-UHFFFAOYSA-N 4-Chlorotoluene Chemical compound CC1=CC=C(Cl)C=C1 NPDACUSDTOMAMK-UHFFFAOYSA-N 0.000 claims description 3
• 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 3
• 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 3
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
• 208000002495 Uterine Neoplasms Diseases 0.000 claims description 3
• 125000003545 alkoxy group Chemical group 0.000 claims description 3
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
• 210000004556 brain Anatomy 0.000 claims description 3
• 210000000481 breast Anatomy 0.000 claims description 3
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
• 229910052794 bromium Inorganic materials 0.000 claims description 3
• 208000029742 colonic neoplasm Diseases 0.000 claims description 3
• 210000003238 esophagus Anatomy 0.000 claims description 3
• 208000014951 hematologic disease Diseases 0.000 claims description 3
• 210000000987 immune system Anatomy 0.000 claims description 3
• 210000004185 liver Anatomy 0.000 claims description 3
• 208000003747 lymphoid leukemia Diseases 0.000 claims description 3
• 201000001441 melanoma Diseases 0.000 claims description 3
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
• 229910052760 oxygen Inorganic materials 0.000 claims description 3
• 239000001301 oxygen Substances 0.000 claims description 3
• 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
• 230000000861 pro-apoptotic effect Effects 0.000 claims description 3
• 125000003003 spiro group Chemical group 0.000 claims description 3
• 239000011593 sulfur Chemical group 0.000 claims description 3
• 206010046766 uterine cancer Diseases 0.000 claims description 3
• 210000004291 uterus Anatomy 0.000 claims description 3
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
• 125000006685 (C1-C6) polyhaloalkyl group Chemical group 0.000 claims description 2
• 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 2
• ZVOCBNCKNQJAFL-UHFFFAOYSA-N 1-methylpyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2N(C)C=CC2=C1 ZVOCBNCKNQJAFL-UHFFFAOYSA-N 0.000 claims description 2
• 125000003635 2-dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims description 2
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
• 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
• 206010009944 Colon cancer Diseases 0.000 claims description 2
• 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 230000010933 acylation Effects 0.000 claims description 2
• 238000005917 acylation reaction Methods 0.000 claims description 2
• 125000003342 alkenyl group Chemical group 0.000 claims description 2
• 125000000304 alkynyl group Chemical group 0.000 claims description 2
• 230000002424 anti-apoptotic effect Effects 0.000 claims description 2
• 125000005110 aryl thio group Chemical group 0.000 claims description 2
• 125000004104 aryloxy group Chemical group 0.000 claims description 2
• 239000004305 biphenyl Substances 0.000 claims description 2
• 235000010290 biphenyl Nutrition 0.000 claims description 2
• 229910052799 carbon Inorganic materials 0.000 claims description 2
• 239000003795 chemical substances by application Substances 0.000 claims description 2
• 229910052801 chlorine Inorganic materials 0.000 claims description 2
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
• 239000011737 fluorine Substances 0.000 claims description 2
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
• 125000001041 indolyl group Chemical group 0.000 claims description 2
• 208000014018 liver neoplasm Diseases 0.000 claims description 2
• 125000001624 naphthyl group Chemical group 0.000 claims description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• 238000005897 peptide coupling reaction Methods 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000005936 piperidyl group Chemical group 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• 238000001959 radiotherapy Methods 0.000 claims description 2
• 239000007858 starting material Substances 0.000 claims description 2
• 238000005694 sulfonylation reaction Methods 0.000 claims description 2
• 229940126601 medicinal product Drugs 0.000 claims 2
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
• 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 1
• 125000004185 ester group Chemical group 0.000 claims 1
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 1
• 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims 1
• 210000000936 intestine Anatomy 0.000 claims 1
• UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 748
• 239000000047 product Substances 0.000 description 391
• 230000015572 biosynthetic process Effects 0.000 description 354
• 238000003786 synthesis reaction Methods 0.000 description 354
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 288
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 233
• 239000000243 solution Substances 0.000 description 203
• 238000004896 high resolution mass spectrometry Methods 0.000 description 162
• 239000011541 reaction mixture Substances 0.000 description 152
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 148
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 113
• UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 103
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 103
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 95
• 239000000741 silica gel Substances 0.000 description 88
• 229910002027 silica gel Inorganic materials 0.000 description 88
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 74
• 235000019341 magnesium sulphate Nutrition 0.000 description 74
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 65
• 239000007787 solid Substances 0.000 description 63
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 59
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 53
• VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 50
• 238000000746 purification Methods 0.000 description 47
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 46
• 238000003818 flash chromatography Methods 0.000 description 45
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 42
• 239000012074 organic phase Substances 0.000 description 41
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 37
• 229910052739 hydrogen Inorganic materials 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
• 239000012267 brine Substances 0.000 description 36
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 36
• 239000002904 solvent Substances 0.000 description 32
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
• 239000000284 extract Substances 0.000 description 31
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 28
• 239000003921 oil Substances 0.000 description 27
• 239000012043 crude product Substances 0.000 description 26
• 238000003756 stirring Methods 0.000 description 25
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 22
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• 125000001931 aliphatic group Chemical group 0.000 description 21
• 239000012298 atmosphere Substances 0.000 description 21
• 238000006243 chemical reaction Methods 0.000 description 21
• 239000013058 crude material Substances 0.000 description 21
• 239000001257 hydrogen Substances 0.000 description 21
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 19
• 230000003197 catalytic effect Effects 0.000 description 19
• 238000005481 NMR spectroscopy Methods 0.000 description 18
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
• AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 17
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• 150000003857 carboxamides Chemical class 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• 239000002244 precipitate Substances 0.000 description 14
• MCIIDRLDHRQKPH-UHFFFAOYSA-N 2-methyl-3-phenylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=CC=C1 MCIIDRLDHRQKPH-UHFFFAOYSA-N 0.000 description 13
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
• 238000010898 silica gel chromatography Methods 0.000 description 13
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
• 238000001914 filtration Methods 0.000 description 12
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
• 239000012047 saturated solution Substances 0.000 description 12
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
• 229960000583 acetic acid Drugs 0.000 description 11
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
• 239000007864 aqueous solution Substances 0.000 description 10
• 238000004440 column chromatography Methods 0.000 description 10
• 238000001704 evaporation Methods 0.000 description 10
• 229920006395 saturated elastomer Polymers 0.000 description 10
• 239000000725 suspension Substances 0.000 description 10
• DLPDBBPTTGBGRX-UHFFFAOYSA-N 3,4-dihydro-1h-isoquinoline-2-carboxylic acid Chemical compound C1=CC=C2CN(C(=O)O)CCC2=C1 DLPDBBPTTGBGRX-UHFFFAOYSA-N 0.000 description 9
• 230000006907 apoptotic process Effects 0.000 description 9
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• 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 9
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